Hypophosphatasia (HPP) is a rare, heritable form of rickets or osteomalacia with an incidence as great as one per 2,500 births in Canadian Mennonites and of one per 100,000 births in the general population for the more severe form of the disease. Milder forms are more prevalent. This “inborn error of metabolism” is caused by loss-of-function mutation(s) in the gene (ALPL) that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNALP; a.k.a., liver/bone/kidney type ALP). The biochemical hallmark is subnormal ALP activity in serum (hypophosphatasemia), which leads to elevated blood and/or urine levels of three phospho-compound substrates: inorganic pyrophosphate (PPi), phosphoethanolamine (PEA) and pyridoxal 5′-phosphate (PLP).
HPP features perinatal, infantile, childhood, adult, and odontohypophosphatasia forms, classified historically according to age at diagnosis. Phenotype ranges from almost complete absence of bone mineralization in utero with stillbirth, to spontaneous fractures and dental disease occurring first in adult life. Perinatal lethal HPP (perinatal HPP, or PL-HPP) is expressed in utero and can cause stillbirth. Some neonates survive several days, but suffer increasing respiratory compromise due to the hypoplastic and rachitic disease of the chest. In infantile HPP, diagnosed before six months of age, postnatal development seems normal until onset of poor feeding, inadequate weight gain, and appearance of rickets. Radiological features are characteristic and show impaired skeletal mineralization, sometimes with progressive skeletal demineralization leading to rib fractures and chest deformity. Childhood HPP has highly variable clinical expression. Premature loss of deciduous teeth results from aplasia, hypoplasia, or dysplasia of dental cementum that connects the tooth root with the periodontal ligament. Rickets causes short stature and skeletal deformities including, for example, bowed legs, enlargement of the wrists, knees, and ankles as a result of flared metaphysis. Adult HPP usually presents during middle age, although frequently there is a history of rickets and/or early loss of teeth followed by good health during adolescence and young adult life. Recurrent metatarsal stress fractures are common, and calcium pyrophosphate dihydrate deposition causes attacks of arthritis and pyrophosphate arthropathy. Odontohypophosphatasia is diagnosed when the only clinical abnormality is dental disease and radiological studies and even bone biopsies reveal no signs of rickets or osteomalacia.
The severe clinical forms of HPP are usually inherited as autosomal recessive traits with parents of such patients showing subnormal levels of serum AP activity. For the milder forms of HPP, e.g., adult and odontohypophosphatasia, an autosomal dominant pattern of inheritance has also been documented.
Since the occurrence of HPP is rare, the diagnosis of HPP is usually missed at the early stages of illness. In addition, most HPP symptoms, such as abnormal skull shape, back pain, bone fractures, bone spurs (bumps around the joints), bow legs, bumps in the rib cage, loss of height over time/short stature, and pain in the joints, are similar to symptoms caused by other more common diseases, such as osteogenesis imperfecta, nutritional rickets, osteoarthritis, and osteoporosis. Other factors that are sometimes used to diagnosis HPP include, for example, low levels of alkaline phosphatase (ALP) in the blood, higher than normal levels of calcium in the blood and urine, bone changes (including bowing (bending) of bones in the arms and legs), poor growth, thick wrists and ankles, loose ligaments, bone pain, fractures, premature tooth loss, family history of HPP, and mutations in the ALPL gene.
As HPP patients may develop symptoms (e.g., mineralization defects) with different severity, there is an unidentified subpopulation of HPP patients with minor to none of the typical HPP symptoms, who have been traditionally mis-diagnosed and/or ignored for treatment (such as enzyme replacement with recombinant TNALP). Moreover, many HPP patients have additional symptoms (such as seizures) in addition to their characteristic mineralization defect(s). Thus, there exists a need to identify such patient populations not only for monitoring (and thus early treatment for) potential health deterioration with HPP symptoms, but also for treating symptoms other than mineralization defects with recombinant TNALP.